Oxime carbonates

ABSTRACT

Novel carbonic acid esters are disclosed which are useful in a process for introducing esterified carboxy-type protective groups on amino and/or imino groups in amino and/or imino group-containing compounds for the temporary protection of said amino and/or imino groups. Additionally, processes for preparing said esters are also disclosed. .Iadd.

This Application is a Re-Issue of U.S. Pat. No. 4,014,915, granted March29, 1977 on Application 607,758, filed August 26, 1975. .Iaddend.

The present invention relates to a new carbonic acid ester which isuseful as an agent for introducing esterified carboxy-type protectivegroups on amino and/or imino groups in amino and/or iminogroup-containing compounds and to processes for the preparation thereof.

Further, the present invention relates to a process for the temporaryprotection of amino and/or imino groups in amino and/or iminogroups-containing compounds with esterified carboxy-type protectivegroups.

It is known that temporary protection of amino and/or imino groups isvery important in the field of preparative chemistry as well as indegradation reactions. For example, in peptide-chemistry,penicillin-chemistry, cephalosporin-chemistry, alkaloid-chemistry,determination of the constitution of unknown compounds such as naturalproducts, and the like.

The present invention is based on the observation that a carbonic acidester, represented by formula (I) as shown below is a much morefavorable agent for the temporary protection of amino and/or iminogroups in the compound in comparison with the agents which have beenconventionally employed in the art. For example,

1. the carbonic acid ester is present in stable oil or crystals and doesnot exhibit explosiveness, corrosiveness or irritativeness which areoften exhibited by conventional agents. It is much more favorable andsafe for handling in experimental as well as industrial use,

2. the carbonic acid ester can be easily prepared and

3. reacts rapidly with amino and/or imino group-containing organiccompounds under milder reaction conditions to give protected aminoand/or imino group-containing compounds. This undesired side reactionsand by-products, often associated with conventional agents, can beminimized or in some case substantially avoided. In the reaction ofcarbonic acid esters with the amino and/or imino group-containingcompounds, there may be produced a compound of the formula:

    R.sub.2 --OH,

wherein R₂ is as defined below. This compound is substantially the soleby-product and is easily recovered in pure form from the reactionmixture by conventional means such as extraction. Further, the compoundmay be used repeatedly as a starting material without any furtherpurification, for the preparation of the compound (I) of the presentinvention.

Accordingly, the present invention provides a process for the protectionof amino and/or imino groups in an amino and/or imino group-containingcompounds, which comprises reacting an amino and/or iminogroup-containing compound with a carbonic acid ester of the formula:

    R.sub.1 OCOOR.sub.2                                        (I).

wherein

R₁ is lower alkyl which may have substituents selected from the groupconsisting of halogen, lower alkoxy and aryloxy, or ar(lower)alkyl whichmay have substituents selected from the group consisting of loweralkoxy, halogen, nitro and cyano, and

R₂ is benzotriazolyl which may be substituted with halogen; or a grouprepresented by the formula: ##STR1## wherein Y and Z are each aryl whichmay have substituents selected from the group consisting of halogen,lower alkoxy, nitro, cyano and halo(lower)alkyl, or an electronwithdrawing group.

According to said reaction, the esterified carboxy group (R₁ OCO--) inthe carbonic acid ester (I) can be introduced to the amino and/or iminogroups in the amino and/or imino group-containing compounds for thepurpose of protecting said groups in said compound.

For this purpose, there may be used as starting material any desiredamino and/or imino group-containing compound, especially an organiccompound including all aliphatic, aromatic or a heterocyclic compounds,etc., each of which contains at least one amino or imino group in themolecule.

In this specification and claims, the term "lower" is intended to mean agroup having 1 to 6 carbon atoms unless otherwise indicated.

A suitable example of lower alkyl for R₁ includes straight chain,branched or cyclic lower alkyls, having 1 to 6 carbon atoms. Examples ofthese lower alkyls include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tertbutyl, pentyl, neopentyl, tert-pentyl, hexyl,1-cyclopropylethyl, cyclopropyl, cyclopentyl, cyclohexyl or the like. Itis preferred that the lower alkyls have 2 to 5 carbon atoms and mayoptionally have at least one substituent selected from the groupconsisting of halogen (e.g., chlorine, bromine, fluorine, or iodine),lower alkoxy having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.) and aryloxyhaving 6 to 10 carbon atoms (e.g., phenoxy, tolyloxy, xylyloxy,naphthyloxy, etc.).

A suitable example of ar(lower)alkyl for R₁ includes those groups having7 to 10 carbon atoms such as benzyl, phenethyl, tolylmethyl,xylylmethyl, mesitylmethyl or the like. It is preferred that thear(lower)alkyl have 7 to 8 carbon atoms and may optionally have at leastone substituent selected from the group consisting of the aforementionedlower alkoxy, halogen, nitro and cyano.

A suitable example of aryl for Y and Z includes those having 6 to 10carbon atoms such a phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl orthe like, and these aryl groups may optionally have at least onesubstituent selected from the group consisting of the aforementionedhalogen, lower alkoxy, nitro, cyano and halo(lower)alkyl (e.g.,trichloromethyl, trifluoromethyl, etc.).

A suitable electron withdrawing group for Y and Z includes cyano, nitro,an acyl such as lower alkanoyl having 1 to 6 carbon atoms (e.g., formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,etc.), aroyl having 7 to 11 carbon atoms (e.g., benzoyl, toluoyl,xyloyl, naphthoyl, etc.), esterified carboxy, for example, loweralkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxycarbonyl,cyclohexyloxycarbonyl, etc.), ar(lower)alkoxycarbonyl having 8 to 9carbon atoms (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.) oraryloxycarbonyl having 7 to 8 carbon atoms (e.g., phenoxycarbonyl,tolyloxycarbonyl, etc.), carbamoyl, disubstituted carbamoyl, forexample, di(lower)alkylcarbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, methylethylcarbamoyl, dipropylcarbamoyl,diisopropylcarbamoyl, dibutylcarbamoyl, etc.), lower alkylarylcarbamoyl(e.g., methylphenylcarbamoyl, ethylphenylcarbamoyl, etc.) ordiarylcarbamoyl (e.g., diphenylcarbamoyl, ditolylcarbamoyl, etc.) or thelike.

A suitable example of benzotriazolyl for R₂ may include1H-benzotriazolyl or 2H-benzotriazolyl and these groups may contain atleast one of the aforementioned halogens.

The present reaction may be conducted in a conventional manner (i.e.under conditions known in the art for using an esterified carboxy groupto protect amino and/or imino groups in the compound). Moreparticularly, the reaction may be conducted in a conventional solventsuch as water, an alcohol (e.g., methanol, ethanol, propyl alcohol,butyl alcohol, tert-butyl alcohol, etc.), ethyl acetate, chloroform,dimethylformamide, methylene chloride, tetrahydrofuran, acetone or thelike, or a mixture thereof, or other solvents which do not adverselyaffect the present reaction. The reaction may be optionally carried outin the presence of a base such as an inorganic base, for example, analkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), an alkaline earth metal hydroxide (e.g., calcium hydroxide,magnesium hydroxide, etc.), an alkali metal carbonate (e.g., sodiumcarbonate, potassium carbonate, etc.), an alkaline earth metal carbonate(e.g., calcium carbonate, magnesium carbonate, etc.), an alkali metalbicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), orthe like; an organic base, for example, an alkali metal acetate (e.g.,sodium acetate, potassium acetate, etc.), trialkylamine (e.g.,trimethylamine, triethylamine, etc.), triethanolamine,N,N-dimethylaniline, N,N-dimethylbenzylamine, N,N'-dimethylpiperazine,N-methylmorpholine, pyridine, quinoline, or the like; or a basicion-exchange resin, or a mixture thereof.

The reaction temperature is not particularly limited, but the reactionis preferably carried out around room temperature.

The product having the protected amino and/or imino group(s) thusprepared can be isolated by a conventional method.

The protected amino and/or imino groups-containing compound can be usedfor further synthesis of known or new compounds in which it is necessaryto protect the amino and/or imino groups in the compound in order toavoid any side-reaction, production of by-product and the like. Theprotected amino and/or imino groups-containing product thus synthesized,may be subsequently subjected releaved of the protective group (i.e.,esterified carboxy group) in order to regenerate the free amino and/orimino group-containing compound. Such subsequent removal of theesterified carboxy type protective groups can be carried out by aconventional method.

The representative examples of the present carbonic acid ester (I) maybe illustrated as follows.

2-Lower alkoxycarbonyloxyimino-2-cyanoacetamide (e.g.,2-ethoxycarbonyloxyimino-2-cyanoacetamide,2-isobutoxycarbonyloxyimino-2-cyanoacetamide or2-methoxycarbonyloxyimino-2-cyanoacetamide), di(lower)alkyl 2-loweralkoxycarbonyloxyiminomalonate (e.g., diethyl2-ethoxycarbonyloxyiminomalonate or diethyl2-tertbutoxycarbonyloxyiminomalonate), lower alkyl 2-loweralkoxycarbonyloxyimino-2-cyanoacetate (e.g., ethyl2-ethoxycarbonyloxyimino-2-cyanoacetate, ethyl2-isobutoxycarbonyloxyimino-2-cyanoacetate, ethyl2-methoxycarbonyloxyimino-2-cyanoacetate or ethyl2-tert-pentyloxycarbonyloxyimino-2cyanoacetate), lower alkyl2-halo(lower)alkoxycarbonyloxyimino-2-cyanoacetate [e.g., ethyl2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-cyanoacetate], lower alkyl2-ar(lower)alkoxycarbonyloxyimino-2-cyanoacetate (e.g., ethyl2-benzyloxycarbonyloxyimino-2-cyanoacetate), lower alkyl 2-loweralkoxycarbonyloxyiminoacetoacetate (e.g., ethyl2-tert-butoxycarbonyloxyiminoacetoacetate), di(lower)alkyl 2-loweralkoxy substituted ar(lower)alkoxycarbonyloxyiminomalonate [e.g.,diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate], 2-loweralkoxycarbonyloxyimino-1-aryl(lower)alkane-1,3-dione (e.g.,2-tert-butoxycarbonyloxyimino-1-phenylbutane-1,3-dione), 1-loweralkoxycarbonyloxy-6-halobenzotriazole (e.g.,1-tert-butoxycarbonyloxy-6-chloro-1H-benzotriazole or1-ethoxycarbonyloxy-6-chloro-1H-benzotriazole), 1-ar(lower)alkoxycarbonyloxybenzotriazole (e.g.,1-benzyloxycarbonyloxy-1H-benzotriazole), 2-loweralkoxycarbonyloxyimino-2-arylacetonitrile [e.g.,2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile,2-tert-butoxycarbonyloxyimino-2-(1-naphthyl) acetonitrile or2-(1-cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile], 9 ,benzophenone O-lower alkoxycarbonyloxime (e.g., benzophenoneO-tert-butoxycarbonyloxime),2-halo(lower)alkoxycarbonyloxyimino-2-arylacetonitrile [e.g.,2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile], 2-loweralkoxy substituted or unsubstitutedar(lower)alkoxycarbonyloxyimino-2-arylacetonitrile [e.g.,2-(4-methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile or2-benzyloxycarbonyloxyimino-2-phenylacetonitrile], 2-loweralkoxycarboxyloxyimino-2-halogen substituted arylacetonitrile [e.g.,2-tert-butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile]or thelike.

The carbonic acid ester of the formula (I) includes new and knowncompounds and the present invention also provides new carbonic acidesters and processes for the preparation thereof.

The new carbonic acid ester is represented by the following formula:

    R'.sub.1 OCOOR'.sub.2                                      I'.

wherein R'₁ is lower alkyl which may have substituents selected from thegroup consisting of halogen, lower alkoxy and aryloxy, or ar(lower)alkylwhich may have substituents selected from the group consisting of loweralkoxy, halogen, nitro and cyano, and

R'₂ is benzotriazolyl which may have halogen; or a group represented bythe formula: ##STR2## wherein Y' and Z' are each aryl which may havesubstituents selected from the group consisting of halogen, loweralkoxy, nitro, cyano and halo(lower)alkyl; cyano; nitro, carbamoyl;esterified carboxy, lower alkanoyl, aroyl or disubstituted carbamoyl;

provided that when R'₂ is a group represented by the formula: ##STR3##wherein Y' and Z' are each cyano, nitro, carbamoyl or esterifiedcarboxy,

R'₁ is ar(lower)alkyl having substituents selected from the groupconsisting of lower alkoxy, halogen, nitro and cyano;

and further provided that when R'₁ is lower alkyl and R'₂ is a grouprepresented by the formula: ##STR4## wherein Y' is cyano and Z' is aryl,the number of carbon atoms of lower alkyl for R'₁ is 4 or 5.

Suitable examples of lower alkyl and ar(lower)alkyl for R'₁ and thesubstituents thereof may be the same as those as illustrated as examplesfor the definition for R₁, respectively.

Suitable examples of aryl, the substituents thereof, esterified carboxy,lower alkanoyl, aroyl and disubstituted carbamoyl for Y' and Z' may bethe same as those illustrated as examples for the definitions of Y andZ. Suitable examples of benzotriazolyl and the substituent thereof forR'₂ may be the same as those illustrated as examples for the definitionof R₂.

The new carbonic acid ester of the formula (I') can be prepared byreacting a haloformic acid ester of the formula:

    X--COOR'.sub.2                                             II.

wherein X is halogen and R'₂ is as defined above, with ahydroxy-compound of the formula:

    R'.sub.1 --OH                                              III.

wherein R'₁ is as defined above.

Suitable examples of halogen for X are the same as those illustrated assubstituents for lower alkyl in the definition of R₁.

The reaction of the compound (II) with the compound (III) is usuallycarried out in a conventional solvent such as chloroform,tetrahydrofuran, ether, acetonitrile, ethyl acetate, acetone, benzene,n-hexane, petroleum ether, dioxane or any other organic solvent whichdoes not adversely affect the reaction. The above reaction includes theuse of these solvents individually or in combination. The reaction ispreferably carried out in the presence of a base such as inorganic base,for example, alkali metal hydroxide (e.g., sodium hydroxide, potassiumhydroxide, etc.), alkaline earth metal hydroxide (e.g., calciumhydroxide, magnesium hydroxide, etc.), alkali metal carbonate (e.g.,sodium carbonate, potassium carbonate, etc.), alkaline earth metalcarbonate (e.g., calcium carbonate, magnesium carbonate, etc.), alkalimetal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate,etc.) or the like. In addition organic bases cn be used such astrimethylamine, triethylamine, triethanolamine, dimethylaniline,pyridine, quinoline, etc. These bases may be used alone or incombination. The reaction temperature is not critical, and the reactionis preferably carried out around room temperature or at a comparativelylower temperature.

Alternatively, the new carbonic acid ester (I') can be prepared byreacting a formic acid ester of the formula:

    R'.sub.1 --OCOX'                                           IV.

wherein R'₁ is as defined above and X' is halogen, with a compound ofthe formula:

    R'.sub.2 --OH                                              V.

wherein R'₂ is as defined above or a salt thereof.

Suitable examples of halogen of X' are the same as those illustrated assubstituents for lower alkyl in the definition of R₁.

The suitable salts of compound (V) are the same as those examplifiedbelow for compound (VI).

In the present reaction, there can be employed similar solvents, basesand reaction temperature as those employed in the reaction of compound(II) with compound (III) as mentioned above. In addition, water or watermixed with the solvents mentioned above may also be used optionallydepending on the properties of compound (IV).

Compound (I') can be also prepared by reacting a mixture of compounds(V) or a salt thereof, (III) and (VII) or a reactive equivalent thereof,in which the reaction may proceed via the same mechanism used forreacting compound (II) with compound (III) and/or reacting compound (IV)with compound (V).

Starting compound (II), for use in the above process, includes partiallynew compounds, which are represented by the following formula:

    X--COOR'.sub.2                                             II'.

wherein

X is as defined above and

R'₂ is benzotriazolyl which may have halogen; or a group represented bythe formula: ##STR5## wherein Y" is aryl which may have substituentsselected from the group consisting of halogen, lower alkoxy, nitro,cyano and halo(lower)alkyl, cyano, nitro, carbamoyl, esterified carboxy,lower alkanoyl, aroyl or disubstituted carbamoyl and

Z" is naphthyl, aryl having substituents selected from the groupconsisting of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl,lower alkanoyl, aroyl or disubstituted carbamoyl.

The new starting compound (II') can be prepared by reacting a compoundof the formula:

    R".sub.2 --OH                                              VI.

wherein R"₂ is as defined above, or a salt thereof with a carbonylhalide of the formula:

    COX.sub.2                                                  VII.

wherein X is as defined above, or a reactive equivalent thereof.

A suitable salt of compound VI may include an alkali metal salt (e.g.,sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g.,calcium salt, magnesium salt, etc.) or the like.

A suitable reactive equivalent of compound (VII) may include polymers ofcompound (VII), for example, the dimer (trichloromethyl chloroformate)or trimer [di(trichloromethyl)carbonate] of compound (VII), in which thesuitable halogen for X is chlorine.

The reaction of compound (VI) with compound (VII) is usually carried outin a conventional solvent such as benzene, toluene, tetrahydrofuran,dioxane or any other organic solvent which does not adversely effect thereaction. The solvent may be used alone or in combination. The reactionis preferably carried out in the presence of a base such as an inorganicbase for example, alkali metal hydroxide (e.g., sodium hydroxide,potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g.,calcium hydroxide, magnesium hydroxide, etc.), alkali metal carbonate(e.g., sodium carbonate, potassium carbonate, etc.), alkaline earthmetal carbonate (e.g., calcium carbonate, magnesium carbonate, etc.),alkali metal bicarbonate (e.g., sodium bicarbonate, potassiumbicarbonate, etc.) or an the like, or organic base (e.g., triethylamine,pyridine, dimethylaniline, etc.). The reaction temperature is notcritical, and the reaction is preferably carried out under cooling orabout room temperature.

In this process, compound (II'), may be isolated from the reactionmixture. In addition the reaction mixture per se can be preferablyemployed for the successive reaction with compound (III) withoutisolating compound (II').

Among the carbonic acid esters of formula (I) and the haloformic acidesters of formula (II), known compound also can be prepared according tosubstantially the same method as mentioned in the explanation of theprocesses for preparing the new carbonic acid ester (I') and the newhaloformic acid ester of formula (II'), respectively.

The following examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1 [Process for the protection of amino and/or imino group(s)]

A. Triethylamine (0.42 ml.) was added to a suspension ofD-2-(3-mesylaminophenyl)glycine (488 mg.) and diethyl2-tertbutoxycarbonyloxyiminomalonate (770 mg.) in a mixture of tertbutylalcohol (10 ml.) and water (10 ml.) The mixture was stirred for 1.5hours at room temperature. Water and a sodium bicarbonate aqueoussolution were added to the reaction mixture followed by ethyl acetate.The resulting mixture was adjusted to pH 7 with a citric acid aqueoussolution. The aqueous layer was separated, washed with ethyl acetate,adjusted to pH 3.5 with a citric acid aqueous solution and extractedwith ethyl acetate. The extract was washed with water, dried overmagnesium sulfate and concentrated to giveN-tert-butoxycarbonyl-D-2-(3-mesylaminophenyl)glycine (634 mg.).

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 SO,                     ______________________________________                                        δ]                                                                      ppm            7.00-  7.60 (5H, m)                                                                  5.11 (1H, d, J = 8Hz)                                                         3.00 (3H, s)                                                                  1.40 (9H, s)                                            ______________________________________                                    

B. D-2-(3Mesylaminophenyl)glycine (2.44 g.) was suspended in a mixtureof methanol: water (1:1) (volume ratio) (25 ml.) and dissolved by addingtriethylamine (2.1 ml.). A solution of diethyl2-tertbutoxycarbonyloxyiminomalonate (3.47 g.) in methanol (15 ml.) wasadded dropwise to the above solution over 10 minutes at 10° to 15° C.The resulting mixture was stirred for 2 hours at room temperature. Thesolvent was distilled off under reduced pressure to about 1/3 of thewhole volume of the reaction mixture and water (30 ml.) plus a saturatedsodium bicarbonate aqueous solution (10 ml.) were added to the residue.Ethyl acetate (40 ml.) and 0.5N hydrochloric acid (26 ml.) were added tothe mixture and then the mixture was shaken. The aqueous layer wasseparated and ethyl acetate (100 ml.) was added thereto, the mixture wasthen adjusted to pH 7.20 with 0.5N hydrochloric acid (12 ml.). Theaqueous layer was again separated, adjusted to pH 2.6 with 0.5Nhydrochloric acid (27 ml.). This was followed by addition of a saturatedsodium chloride aqueous solution and the aqueous layer was extractedtwice with ethyl acetate (150 ml.). The extract was washed with asaturated sodium chloride aqueous solution, dried over magnesium sulfateand treated with activated charcoal. The solvent was distilled off underreduced pressure to giveN-tert-butoxycarbonyl-D-2-(3-mesylaminophenyl)glycine (3.50 g.).

C. A solution of diethyl 2-tert-butoxycarbonyloxyiminomalonate (700 mg.)in acetone (5 ml.) was added dropwise to a solution ofD-2-(3-mesylaminophenyl)glycine (488 mg.) and triethylamine (0.42 ml.)in a mixture of acetone (5 m.) and water (5 ml.) over 5 minutes at roomtemperature. The mixture was stirred for 2 hours at the sametemperature. The reaction mixture was concentrated under reducedpressure. A sodium bicarbonate aqueous solution and water were added tothe residue which brought the pH of the solution to about between 9 and10. The solution was adjusted to pH 7 with a 0.5M citric acid aqueoussolution and washed with ethyl acetate. This aqueous solution wasadjusted to pH 3.5 with a 0.5M citric acid aqueous solution andextracted twice with ethyl acetate (30 ml.). The extract was washed witha sodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to giveN-tert-butoxycarbonyl-D-2-(3-mesylaminophenyl)glycine (672 mg.), gummy.

D. A solution of diethyl 2-tert-butoxycarbonyloxyiminomalonate (1.9 g.)in tert-butyl alcohol (5 ml.) was added to a solution of L-isoleucine(656 mg.) in a 1N sodium hydroxide aqueous solution (5.0 ml). Themixture was stirred for 3 hours at room temperature. The tert-butylalcohol was removed from the reaction mixture under reduced pressure andwater was added to the residue. The mixture was washed with ether,adjusted to pH 3 with a 5% citric acid aqueous solution and extractedwith ethyl acetate. The extract was washed with water, dried andconcentrated to give N-tert-butoxycarbonyl-Lisoleucine (1.2 g.), oil.

E. Diethyl 2-tert-butoxycarbonyloxyiminomalonate (1.93 g.) was added toa solution of N^(G) -nitro-L-arginine (1.1 g.) and sodium bicarbonate(0.63 g.) in a mixture of water (50 ml.) and tert-butyl alcohol (20ml.). The mixture was stirred for 3 hours at room temperature. Thereaction mixture was adjusted to pH 7.0 with a citric acid aqueoussolution, washed with ethyl acetate, adjusted to pH 3 with a citric acidaqueous solution and extracted with ethyl acetate (100 ml.). The extractwas washed with water, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was crystallized with a mixture ofethyl acetate and petroleum ether and the precipitates were collected byfiltration to give N.sup.α -tert-butoxycarbonyl-N^(G) -nitro-L-arginine(1.1 g.), mp 114° to 116° C. (dec.).

F. L-Phenylalanine (330 mg.) and sodium bicarbonate (202 mg.) weredissolved in water (10 ml.) under heating and allowed to stand. Asolution of diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0g.) in tert-butyl alcohol (10 ml.) was added to the solution withstirring at room temperature and water (10 ml.) was added thereto, themixture was then stirred for 2 hours at room temperature. The reactionmixture was brought to pH 9 by adding water (20 ml.) and saturatedsodium bicarbonate aqueous solution (10 ml.), and water (10 ml.) wasadded thereto. The resulting mixture was then washed twice with ethylacetate (20 ml.). The aqueous layer was adjusted to pH 7 with a 10%citric acid aqueous solution, washed twice with ethyl acetate (30 ml.),adjusted to pH 3.5 with a 10% citric acid aqueous solution and extractedthree times with ethyl acetate (30 ml.). The extract was washed with asodium chloride aqueous solution and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure to giveN-(4-methoxybenzyloxycarbonyl)-L-phenylalanine (410 mg.), oil.

G. A solution of ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate (646mg.) in a mixture of tert-butyl alcohol (5 ml.) and water (5 ml.) wasadded at once to a solution of L-phenylalanine (330 mg.) andtriethylamine (0.28 ml.) in a mixture of tert-butyl alcohol (8 ml.) andwater (8 ml.) at room temperature. The mixture was stirred for 2 hoursat room temperature. Water (100 ml.) was added to the reaction mixtureand the mixture was adjusted to pH 7 with a 0.5M citric acid aqueoussolution and washed twice with ethyl acetate (40 ml). The aqueous layerwas adjusted to pH 3 with a 0.5M citric acid aqueous solution, followedby addition of a sodium chloride aqueous solution, and extracted twicewith ethyl acetate (40 ml.). The extract was washed with water anddried. The solvent was distilled off under reduced pressure to giveN-tert-butoxycarbonyl-L-phenylalanine (286 mg.).

H. Triethylamine (1.68 ml.) was added to a suspension of L-alanine (0.89g.) in a mixture of water (5 ml.) and tert-butyl alcohol (5 ml.) to givehomogeneous solution. Diethyl 2-tert-butoxycarbonyloximinomalonate (4.0g.) was added to the solution and the mixture was stirred for 1 hour atroom temperature. tert-Butyl alcohol was distilled off from the reactionmixture under reduced pressure and ether and a 5% sodium bicarbonateaqueous solution were added to the residue. The resulting mixture wasadjusted to pH 7 with a citric acid aqueous solution. The aqueous layerwas separated and ethyl acetate was added thereto. The mixture was thenadjusted to pH 3 with a citric acid aqueous solution. The mixture wasadequately shaken and the ethyl acetate layer was separated, washed withwater and dried. The solution was concentrated under reduced pressureand the residue was recrystallized from a mixture of ether and petroleumether to give N-tert-butoxycarbonyl-L-alanine (1.59 g.), mp 82° to 84°C.

I. A suspension of 1-tert-butoxycarbonyloxy-6-chloro-1H-benzotriazole(2.7 g.), L-isoleucine (1.3 g) and triethylamine (3.5 ml.) in a mixtureof water (8 ml.) and tert-butyl alcohol (12 ml.) was stirred for 2 hoursat 60° to 62° C. tert-Butyl alcohol was distilled off from the reactionmixture under reduced pressure and water (15 ml.) was added to theresidue. The mixture was adjusted to pH 3 with a citric acid aqueoussolution under ice-cooling and extracted with ethyl acetate. The extractwas then washed with water and a saturated sodium chloride aqueoussolution. The thus formed precipitates were filtered off and then thefiltrate was dried over magnesium sulfate. The solution was concentratedand a mixture of ether and petroleum ether (1:1) was added to theresidue. An insoluble material was filtered off and the filtrate wasconcentrated under reduced pressure to giveN-tert-butoxycarbonyl-L-isoleucine (2.4 g.), oil.

Infrared Absorption Sprectrum (Film): 2980, 1725 (shoulder), 1710, 1165cm⁻¹.

J. A solution of diethyl 2-tert-butoxycarbonyloxyiminomalonate (4.5 g.)in tert-butyl alcohol (40 ml.) was added at once to a solution ofD-2-(3-dimesylaminophenyl)glycine (3.22 g.) and sodium bicarbonate (1.26g.) in a mixture of tert-butyl alcohol (80 ml.) and water (120 ml.)under ice-cooling and stirring. After stirring for 1.5 hours at roomtemperature, an insoluble material was filtered off. The filtrate wasadjusted to pH 7.5 with a 0.2M citric acid aqueous solution andtert-butyl alcohol was distilled off under reduced pressure. The residuewas washed with ether and adjusted to pH 3 with a 0.2M citric acidaqueous solution. The aqueous solution was saturated with sodiumchloride and extracted with ethyl acetate. The extract was washed with asaturated sodium chloride aqueous solution and dried, and the solventwas distilled off under reduced pressure to giveN-tert-butoxycarbonyl-D-2-(3-dimesylaminophenyl)-glycine (2.1 g.), foamysolid.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub. 2 SO,                    ______________________________________                                        δ]                                                                      ppm                7.50 (4H, m)                                                                  5.20 (1H, d)                                                                  3.33 (6H, s)                                                                  1.40 (9H, s)                                               ______________________________________                                    

K. N-tert-Butoxycarbonyl-L-phenylalanine was obtained according to amethod similar to that of Example 1 (G) by using L-phenylalanine and2-tert-butoxycarbonyloxyimino-1-phenylbutane-1,3-dione.

L. N-Benzyloxycarbonyl-L-phenylalanine was obtained according to amethod similar to that of Example 1 (G) by using L-phenylalanine andethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate.

M. 6-Benzyloxycarbonylaminopenicillanic acid was obtained according to amethod similar to that of Example 1 (G) by using 6-aminopenicillanicacid and ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate.

N. 2-(4-Methoxybenzyl)oxycarbonyloxyimino-2-phenylacetonitrile (1.55 g.)was added to a solution of L-phenylalanine (826 mg.) and triethylamine(0.75 ml.) in a mixture of methanol (10 ml.), dioxane (1.5 ml.) andwater (7.5 ml.) at room temperature the resulting mixture was stirredfor 2 hours at room temperature. The reaction mixture was concentratedand benzene and a sodium bicarbonate aqueous solution were added to theresidue. After shaking the resultant mixture, the aqueous layer wasseparated from the mixture, washed with ether, acidified withhydrochloric acid and extracted with ethyl acetate. The extract waswashed with water, dried and concentrated. N-Hexane was added to theresidue, and the precipitated crystals were collected by filtration anddried to give N-(4-methoxybenzyl)oxycarbonyl-L-phenylalanine (1.064 g.),mp 87° to 88° C.

O. 2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile (1.25 g.) wasadded to a solution of L-proline (575 mg.) and triethylamine (0.7 ml.)in a mixture of methanol (7.5 ml.), dioxane (2.5 ml.) and water (5.0ml.) at room temperature. The reaction mixture was concentrated underreduced pressure and benzene and water were added to the residue. Aftershaking the resultant mixture, the aqueous layer was separated from themixture, washed with benzene, acidified with hydrochloric acid, andextracted with ethyl acetate. The extract was washed with water, driedover magnesium sulfate and concentrated. A mixture of ether and n-hexanewas added to the residue and the residue was added a mixture of etherand n-hexane and the precipitated crystals were collected by filtrationand dried to give N-tert-butoxycarbonyl-L-proline (845 mg.), mp (845mg.), mp 133° to 134° C.

P. According to a method similar to that of Example 1 (O),N-tert-butoxycarbonyl-L-leucine hemihydrate (899 mg.), mp 78° to 84° C.,was obtained by using L-leucine (656 mg.) and2-tertbutoxycarbonyloxyimino-2-phenylacetonitrile (1.35 g.) as startingmaterials.

Q. According to a method similar to that of Example 1 (O),N-tert-butoxycarbonyl-L-methionine dicyclohexylamine salt (1.768 g.), mp137° to 139° C., was obtained by using L-methionine (746 mg.) and2-tertbutoxycarbonyloxyimino-2-phenylacetonitrile (1.35 g.) as startingmaterials.

R. According to a method similar to that of Example 1 (O),N-tert-butoxycarbonyl-L-phenylalaninedicyclohexylamine salt (1.463 g.)mp 222° to 223° C. (dec.), was obtained by using L-phenylalanine (826mg.) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1.25 g.) asstarting materials.

S. According to a method similar to that of Example 1 (O),N-tert-butoxycarbonyl-L-asparagine (918 mg.), mp 166° to 167° C. (dec.),was obtained by using L-asparagine hydrate (0.75 g.) and2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1.85 g.) as startingmaterials.

T. According to a method similar to that of Example 1 (O), N.sup.α-tert-butoxycarbonyl-N^(G) -nitro-L-arginine (2.56 g.), mp 123° to 125°C., was obtained by using N^(G) -nitro-L-arginine (2.20 g.) and2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (2.71 g.) as startingmaterials.

U. According to a method similar to that of Example 1 (O),N-tert-butoxycarbonyl-L-threonine dicyclohexylamine salt (5.50 g.), mp152° to 153° C., was obtained by using L-threonine (2.4 g.) and2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (5.4 g.) as startingmaterials.

V. According to a method similar to that of Example 1 (O),N-tert-butoxycarbonylglycine (1.523 g.), mp 86.5° to 87.5° C., wasobtained by using glycine (0.75 g.) and2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (2.71 g.) as startingmaterials.

W. According to a method similar to that described in the foregoingExamples 1 (A) and 1 (V), the process for the protection of amino and/orimino groups gives similar results and is carried out by using thefollowing various carbonic acid esters.

1. 2-Ethoxycarbonyloxyimino-2-cyanoacetamide, mp 194° to 196° C.

2. Diethyl 2-ethoxycarbonyloxyiminomalonate, oil.

3. Ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate, oil.

4. 2-Isobutoxycarbonyloxyimino-2-cyanoacetamide, mp 156° to 158° C.

5. Ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate, mp 60° to 62° C.

6. 2-Methoxycarbonyloxyimino-2-cyanoacetamide, mp 174° to 175° C.(dec.).

7. Ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate, mp 69° to 71° C.

8. Ethyl 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-cyanoacetate, mp51° to 53° C.

9. Ethyl 2-tert-pentyloxycarbonyloxyimino-2-cyanoacetate, oil.

Infrared Absorption Spectrum: 1810, 1740 cm⁻¹.

10. 1-Ethoxycarbonyloxy-6-chloro-1H-benzotriazole, mp 160° to 162° C.

11. 1-Benzyloxycarbonyloxy-1H-benzotriazole, mp 130° to 131° C.

12. Benzophenone O-tert-butoxycarbonyloxime, mp 131° to 133° C.

13. 2-tert-Butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile, mp 91°to 92° C.

14. 2-Benzyloxycarbonyloxyimino-2-phenylacetonitrile, mp 73° to 75° C.

15. 2-tert-Butoxycarbonyloxyimino-2(1-naphthyl)acetonitrile, mp 90° to92° C.

16. 2-(1-Cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile, mp 65°to 67° C.

17. 2-(2,2,2-Trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile, mp82° to 84° C.

EXAMPLE 2 [PREPARATION OF CARBONIC ACID ESTERS]

A. Benzene (20 ml.) was added to a solution of phosgene 2.5 g.) inbenzene (11.4 ml.). A solution of diethyl 2-hydroxyiminomalonate (4.73g.) and N,N-dimethylaniline (3.03 g.) in benzene (30 ml.) was addeddropwise to the solution over 40 minutes at 5° C. in a nitrogen stream.The mixture was stirred for 1 hour at the same temperature and overnightat room temperature. A solution of 4-methoxybenzylalcohol (3.11 g.) andpyridine (4.04 ml.) in benzene (30 ml.) was added dropwise the theresultant mixture containing diethyl 2-chlorocarbonyloxyiminomalonateover a period of 40 minutes at 5° C. The mixture was stirred for 2 hoursat the same temperature, for 3 hours at room temperature and allowed tostand overnight. Cold water (100 ml.) was added to the reaction mixtureto dissolve an insoluble material and cooled 1 N-hydrochloric acid (20ml.) was added thereto, after which the mixture was shaken. The organiclayer was then washed 3 times with 1 N hydrochloric acid (20 ml.), 3times with a 5% sodium carbonate aqueous solution (20 ml.) and a sodiumchloride aqueous solution, and then dried over magnesium sulfate. Afterdrying, the solvent was distilled off to give diethyl2-(4-methoxybenzyloxycarbonyloxyimino)malonate (6.89 g.), a pale brownoil, which was solidified on standing at ambient temperature.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum (CCl.sub.4, δ)                      ______________________________________                                        ppm          6.88   7.38 (4H, ABq, J = 9.0 Hz)                                                    5.23 (2H, s)                                                                  4.39 (4H,q, J =  7.1 Hz)                                                      3.80 (3H, s)                                                                  1.37 (3H, t, J = 7.1 Hz)                                                      1.33 (3H, t, J = 7.1 Hz)                                  ______________________________________                                    

B. A solution of ethyl 2-hydroxyiminoacetoacetate (3.98 g.) and pyridine(1.98 g.) in benzene (25 ml.) was added dropwise to a solution ofphosgene (2.48 g.) in benzene (30 ml.) for 30 minutes at 4° to 5° C.After stirring for 1 hour at the same temperature, the mixture wasstirred for 1 hour at room temperature and allowed to stand overnight. Asolution of tert-butyl alcohol (3.7 g.) and pyridine (3.96 g.) inbenzene (25 ml.) was added dropwise for 30 minutes at 5° to 7° C. to theresultant solution containing ethyl2-chlorocarbonyloxyiminoacetoacetate. After stirring for 1 hour at thesame temperature, the reaction temperature was slowly elevated to roomtemperature, after which the mixture was stirred for 6 hours at the sametemperature and allowed to stand overnight. A precipitate as dissolvedby adding about the same volume of water as that of the organic layer tothe reaction mixture. The aqueous layer was then separated. The organiclayer was then washed with a 0.5 M citric acid aqueous solution, a 5%sodium carbonate aqueous solution and a sodium chloride aqueoussolution, and dried over magnesium sulfate. After drying, the solventwas distilled off to give ethyl2-tert-butoxycarbonyloxyiminoacetoacetate (3.7 g.), oil.

Infrared Absorption Spectrum (Film): 1780, 1730, 1690 cm⁻¹.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum (CCl.sub.4, δ)                      ______________________________________                                        ppm                 4.34 (3H, q)                                                                  2.48 (3H, s)                                                                  1.57 (9H, s)                                                                  1.37 (3H, t)                                              ______________________________________                                    

C. A solution of 2-hydroxyimino-1-phenylbutane-1,3-dione (3.82 g.) andpyridine (1.62 ml.) in benzene (30 ml.) was added dropwise to a solutionof phosgene (1.98 g.) in benzene (25 ml.) for 40 minutes at 5° to 9° C.After stirring for 1 hour at the same temperature, the mixture wasallowed to stand overnight. A solution of tert-butyl alcohol (2.96 g.)and pyridine (3.16 g.) in benzene (30 ml.) was added dropwise for 30minutes at 5° C. to the resultant solution containing2-chlorocarbonyloxyimino-1-phenylbutane-1,3-dione. After stirring for 1hour at the same temperature, the mixture was stirred for 6 hours atroom temperature, after which the mixture was allowed to standovernight. Cooled water (100 ml.) was added to the reaction mixture andthe organic layer was then washed with water, a 0.5 M citric acidaqueous solution (20 ml.) (4 times) and a 5% sodium carbonate aqueoussolution (20 ml.) (4 times) until the aqueous layer became almostcolorless. The organic layer was further washed with a sodium chlorideaqueous solution and then dried over magnesium sulfate. After drying,the solution was treated with activated charcoal and the solvent wasdistilled off to give an oil (3.48 g.). The oil was partly crystallizedby allowing it to stand and ether was then added to the mixture toprecipitate crystals. The precipitates were collected by filtration andrecrystallized from a mixed solvent of carbon tetrachloride andpetroleum ether to give2-tert-butoxycarbonyloxyimino-1-phenylbutane-1,3-dione (350 mg.), mp 90°to 103° C. (dec.).

Infrared Absorption Spectrum (Nujol): 1785, 1700, 1680 cm⁻¹.

Analysis: C₁₅ H₁₇ NO₅ : Calcd.: C, 61.85, H, 5.88, N, 4.81 Found: C,62.00, H, 5.92, N, 4.98

D. A solution of phosgene (5 g.) in benzene (23.5 ml.) was addeddropwise under ice-cooling to a suspension of1-hydroxy-6-chloro-1H-benzotriazole (8.5 g.) and pyridine (3.9 g.) inbenzene (50 ml.). The mixture was stirred for 30 minutes at the sametemperature and allowed to stand overnight. A solution of tert-butylalcohol (3.7 g.) and pyridine (4.0 g.) in benzene (50 ml.) was addeddropwise for 20 minutes under ice-cooling to the resultant solutioncontaining 1-chlorocarbonyloxy-6-chloro-1H-benzotriazole. The resultantmixture was stirred for 2 hours at the same temperature and allowed tostand overnight. The reaction mixture was filtered and the filtrate wasconcentrated. Ether and petroleum ether were added to the residue topulverize the residue and the resultant crystals were collected byfiltration to give 1-tert-butoxycarbonyloxy-6-chloro-1H-benzotriazole(5.3 g.). The mother liquor was concentrated to give the same desiredcompound (0.6 g.). Both quantities of crystals were mixed and dissolvedin benzene. The resultant solution was then washed with a sodiumbicarbonate aqueous solution and water and then dried. The solvent wasremoved by distillation to give the desired compound (3.2 g.), powder,mp 98° to 100° C. (dec.).

Analysis: C₁₁ H₁₂ N₃ O₃ Cl Calcd.: C, 48.98, H, 4.48, N, 15.58, Cl,13.14 Found: C, 49.25, H, 4.32, N, 15.88, Cl, 13.36

E. A solution of 2-hydroxyimino-2-phenylacetonitrile (7.3 g.) anddimethylaniline (6.0 g) in a mixture of benzene (50 ml) and dioxane (5ml.) was added dropwise to a solution of phosgene (5.5 g.) in benzene(50 ml.) over 1 hour at 3° to 5° C. The mixture was stirred for 3.5hours at the same temperature and allowed to stand overnight. A solutionof tert-butyl alcohol (7.4 g.) and pyridine (5.0 ml.) in benzene (20ml.) was added dropwise for 1 hour under ice-cooling to the resultantsolution containing 2-chlorocarbonyloxyimino2-phenylacetonitrile. Theresultant mixture was stirred for 4 hours at the same temperature, andpyridine (3.0 ml.) was added dropwise thereto. The mixture was thenstirred for 1 hour at room temperature and allowed to stand overnight.Water was added thereto and the organic layer was separated. The organiclayer was then washed with 1 N hydrochloric acid (3 times), a sodiumchloride aqueous solution, a sodium bicarbonate aqueous solution (twice)and a sodium chloride aqueous solution (twice) and concentrated. Theresidue was allowed to stand to obtain crystals. The crystals weretriturated in aqueous methanol, collected by filtration, washed withn-hexane and dried to give2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (7.0 g.), mp 84° to86° C.

Infrared Absoprtion Spectrum (Nujol): 1785 cm⁻¹.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, δ)                     ______________________________________                                        ppm                7.3- 8.1 (5H, m)                                                              1.60 (9H, s)                                               ______________________________________                                    

F. A solution of 2-hydroxyimino-2-phenylacetonitrile (7.3 g.),dimethylaniline (6.0 g.) and tert-butyl alcohol (3.7 g.) in benzene (50ml.) was added dropwise to a solution of phosgene (5.0 g.) in benzene(50 ml.) for 30 minutes under ice-cooling. A solution of pyridine (4.0ml.) in benzene (20 ml.) was added dropwise to the mixture. Theresultant mixture was stirred for 1 hour at the same temperature andallowed to stand overnight. Water and benzene were added to the reactionmixture and an insoluble material was filtered off. The organic layerwas then washed with 1 N hydrochloric acid, water, a sodium bicarbonateaqueous solution and water, and dried over magnesium sulfate. Thesolvent was distilled off and n-hexane and a small amount of methanolwere added to the residue. An insoluble material was filtered off andthe filtrate was concentrated. Methanol was added to the residue and themixture was allowed to stand. The precipitates were collected byfiltration to give 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile(3.5 g.), Mp 83° to 85° C. Water was added to the mother liquor and themixture was allowed to stand. The precipitates were collected byfiltration to give the desired compound (1.5 g.). Total yield (5.0 g.).

G. A solution of 2-hydroxyimino-2-phenylacetonitrile (14.6 g.) anddimethylaniline (13.2 g.) in a mixture of acetone (5 ml.) and benzene(80 ml.) was added to a solution of trichloromethyl chloroformate(phosgene dimer) (6.7 ml.) in benzene (30 ml.) under ice-cooling. Themixture was stirred for 6 hours at the same temperature and allowed tostand overnight. A mixture of tert-butyl alcohol (11.1 g.), pyridine(16.0 ml.) and benzene (20 ml.) was added dropwise, under ice-cooling,to the resultant mixture containing2-chlorocarbonyloxyimino-2-phenyl-acetonitrile. The mixture was stirredfor 7 hours at room temperature and allowed to stand overnight. Thereaction mixture was treated as described in the above Examples 2(A) to2(F) to give 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (17.0g.), mp 84° to 86° C.

H. A solution of dimethylaniline (6.0 ml.) in benzene (15 ml.) was addeddropwise to a suspension of 2-hydroxyimino-2-phenylacetonitrile (7.3 g.)and phosgene (5.0 g.) in benzene (50 ml.) for 40 minutes underice-cooling. The mixture was stirred for 2 hours at the same temperatureand allowed to stand overnight. A solution of 4-methoxybenzyl alcohol(6.9 g.) and pyridine (4.0 ml.) in benzene (20 ml.) was added dropwise,for 30 minutes under ice-cooling to the mixture containing2-chlorocarbonyloxyimino-2-phenylacetonitrile. The mixture was stirredfor 7 hours at room temperature. The reaction mixture was then washedwith water, 1 N hydrochloric acid, water, a sodium bicarbonate aqueoussolution and water, and dried over magnesium sulfate. The solution wasconcentrated and the residual crystals were triturated in n-hexane andcollected by filtration. The crystals were recrystallized from a mixtureof ethyl acetate and n-hexane to give2-(4-methoxybenzyl)oxycarbonyloxyimino-2-phenylacetonitrile (3.1 g.). Mp112° to 113° C. The mother liquor was concentrated to give the desiredcompound (2.4 g.). Total yield (5.5 g.).

Infrared Absorption Spectrum (Nujol): 1785 cm⁻¹.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, δ)                     ______________________________________                                        ppm               6.8-   8.0 (9H, m)                                                                   5.30 (2H, s)                                                                  3.80 (3H, s)                                         ______________________________________                                    

Analysis: C₁₇ H₁₄ O₄ N₂ : Calcd.: C, 65.79, H, 4.54, N, 9.03; Found: C,65.99, H, 4.38, N, 9.03.

I. A solution of 2-hydroxyimino-2-phenylacetonitrile (14.6 g) anddimethylaniline (13.2 g.) in a mixture of benzene (80 ml.) and dioxane(8 ml.) was added to a solution of trichloromethyl chloroformate(phosgene dimer) (11 g.) in benzene (50 ml.) under ice-cooling. The andthe mixture was stirred for 3 hours at the same temperature and allowedto stand overnight. A solution of tert-butyl alcohol (14.8 g.) andpyridine (16.0 ml.) in benzene (20 ml.) was added dropwise, underice-cooling, to the mixture containing2-chlorocrabonyloxyimino-2-phenylacetonitrile. The reaction mixture wasstirred for 6 hours and the reaction temperature was gradually elevatedto room temperature and allowed to stand overnight. Water was added tothe reaction mixture and the organic layer was separated. The organiclayer was then washed with 1 N hydrochloric acid, a sodium chlorideaqueous solution, a sodium bicarbonate aqueous solution and water andthen dried. The solvent was distilled off and methanol was added to theresidue. The mixture was cooled with, ice-water and the precipitateswere collected by filtration and washed with a small amount of cooledmethanol to give 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (9.5g.). The desired compound (9.4 g.) was further obtained from the motherliquor. Amounts of the desired compounds obtained above were combinedand recrystallized from methanol to give the pure compound (14.6 g.), mp84° to 86° C.

J. A solution of benzophenone oxime (9.85 g.) and dimethylaniline (6.6g.) in a mixture of benzene (50 ml.) and dioxane (10 ml.) was addeddropwise to a solution of trichloromethyl chloroformate (phosgene dimer)(5.5 g.) in benzene (15 ml.) under ice-cooling. The resultant mixturewas stirred for 1 hour at the same temperature, for 2 hours at roomtemperature and then allowed to stand overnight. A solution oftert-butyl alcohol (5.6 g.) and pyridine (6.0 ml.) in benzene (20 ml.)was added dropwise, under ice-cooling to the resultant mixturecontaining benzophenone O-chlorocarbonyloxime. The mixture was stirredfor 6 hours at the same temperature and allowed to stand overnight. Thereaction mixture was then washed with water, 1 N hydrochloric acid,water, a sodium bicarbonate aqueous solution and water, and dried overmagnesium sulfate. The solvent was distilled off and petroleum ether wasadded to the resulting crystals. The crystals were collected byfiltration and dried to give benzophenone O-tert-butoxycarbonyloxime(10.5 g.), mp 126° to 133° C. A small amount of the crystals wasrecrystallized from a mixture of toluene and petroleum ether to give thepure compound, mp 131° to 133° C.

Infrared Absorption Spectrum (Nujol): 1770 cm⁻¹.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum (CDCl.sub.3 , δ)                    ______________________________________                                        ppm              7.17-  7.65 (10H, m)                                                                 1.48 (9H, s)                                          ______________________________________                                    

K. A suspension of 2-hydroxyimino-2-(4-chlorophenyl)acetonitrile (6.75g.) and dimethylaniline (4.5 g.) in a mixture of dichloromethane (70ml.), dioxane (10 ml.) and tetrahydrofuran (10 ml.) was added dropwiseto a solution of trichloromethyl chloroformate (phosgene dimer) (16 g.)in benzene (22 ml.) under ice-cooling. The mixture was stirred for 5hours at the same temperature and allowed to stand overnight. A solutionof tertbutyl alcohol (8.9 g.) and pyridine (9.6 ml.) in dichloromethane(20 ml.) was added dropwise, under ice-cooling, to the resultant mixturecontaining 2-chlorocarbonyloxyimino-2-(4-chlorophenyl)acetonitrile. Themixture was stirred for 5 hours at the same temperature and allowed tostand for 48 hours. The reaction mixture was then washed with water, 1 Nhydrochloric acid, water, a sodium bicarbonate aqueous solution andwater, and dried over magnesium sulfate. The solvent was distilled offand n-hexane was added to the residue. An insoluble material wasfiltered off and the filtrate was concentrated. Petroleum ether wasadded to the residue and the mixture was allowed to stand to precipitatecrystals. The crystals were dissolved in hot petroleum ether and thesolution was filtered. The filtrate was cooled to precipitate crystalsand the crystals were collected by filtration to give2-tert-butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile (1.6 g.).These crystals were recrystallized from methanol to give the purecompound (0.7 g.), mp 91° to 92° C.

Infrared Absorption Spectrum (Nujol): 1790 cm⁻¹.

    ______________________________________                                        Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, δ)                     ______________________________________                                        ppm            7.90 (2H, ABq, J = 4.5Hz)                                                     7.50 (2H, ABq, J = 4.5Hz)                                                     1.63 (9H, s)                                                   ______________________________________                                    

L:

1. Preparation of the starting compound

2-(1-naphthyl)acetonitrile (16.7 g.) was added to a solution of sodiumhydroxide (4.2 g.) in methanol (80 ml.). Gaseous methyl nitrite whichwas prepared by adding a solution of concentrated sulfuric acid (5 ml.)in water (10 ml.) to a solution of sodium nitrite (8.3 g.) in a mixtureof methanol was introduced, under ice-cooling, and water (5 ml.). Themixture was stirred for 4 hours at the same temperature and the reactionmixture was treated by a conventional method to give2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.1 g.), oil.

Infrared Absorption Spectrum (Film): 1700 cm⁻¹.

2. Preparation of the desired compound

A solution of 2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.0 g.) anddimethylaniline (12.0 g.) in toluene (100 ml.) was added dropwise, underice-cooling, to a solution of trichloromethyl chloroformate (phosgenedimer) (3.56 g.) in benzene (30 ml.). The mixture was stirred for 3hours at the same temperature and allowed to stand overnight. A solutionof tert-butyl alcohol (11.1 g.) and pyridine (12 ml.) in toluene (20ml.) was added dropwise, under ice-cooling, to the resultant mixturecontaining 2-chlorocarbonyloxyimino-2-(1-naphthyl)acetonitrile. Themixture was stirred for 6 hours at the same temperature and allowed tostand overnight. The reaction mixture was then washed with water, 1 Nhydrochloric acid, water, a sodium bicarbonate aqueous solution andwater, and dried over magnesium sulfate. The solution was concentratedunder reduced pressure and n-hexane and methanol were added to theresidue. The mixture was allowed to stand in a refrigerator and theprecipitated crystals were collected by filtration and recrystallizedtwice from methanol to give2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile (3.3 g.), mp90° to 92° C.

Analysis: C₁₇ H₁₆ O₃ N₂ : Calcd.: C, 68.90, H, 5.44, N, 9.46; Found: C,68.85, H, 5.38, N, 9.40.

Infrared Absorption Spectrum (Nujol): 1790 cm⁻¹.

M. A solution of 2-hydroxyimino-2-phenylacetonitrile (2.2 g.) anddimethylaniline (1.80 g.) in a mixture of benzene (25 ml.) and dioxane(3 ml.) was added dropwise to a solution of trichloromethylchloroformate (phosgene dimer) (1.5 g.) in benzene (20 ml.) underice-cooling. The mixture was stirred for 3 hours at the same temperatureand allowed to stand overnight. A solution of 1-cyclopropylethanol (1.4g.) and pyridine (1.2 ml.) in benzene (10 ml.) was added dropwise, underice-cooling, to the resultant mixture containing2-chlorocarbonyloxyimino-2-phenylacetonitrile. The mixture was stirredfor 2 hours at the same temperature, for 4 hours at room temperature andallowed to stand overnight. The reaction mixture was then washed with 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution andwater, and dried over magnesium sulfate. The solvent was distilled offand a small amount of methanol to the oily residue was added a smallamount of methanol. The mixture was allowed to stand in a refrigeratorand the precipitated crystals were collected by filtration andrecrystallized from methanol to give2-(1-cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile (0.7 g.),mp 65° to 67° C.

Infrared Absorption Spectrum (Nujol): 1785 cm⁻¹.

Analysis: C₁₄ H₁₄ O₃ N₂ : Calcd.: C, 65.10, H, 5.46, N, 10.85; Found: C,65,07, H, 5.15, N, 10.84.

N. The following compounds were obtained according to a method similarto those described in Examples 2(A) to 2(M).

1. 1-Ethoxycarbonyloxy-6-chloro-1H-benzotriazole, mp 160° to 162° C.

2. 1-Benzyloxycarbonyloxy-1H-benzotriazole, mp 130° to 131° C.

3. 2-Benzyloxycarbonyloxyimino-2-phenylacetonitrile, mp 73° to 75° C.

4. 2-(2,2,2-Trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile, mp82° to 84° C.

EXAMPLE 3 [Preparation of carbonic acid esters]

A. Ether (10 ml.) was added to a solution of phosgene (2 g.) in benzene(12.4 ml.). A solution of 4-methoxybenzyl alcohol (2.76 g.) in ether (10ml.) was added dropwise to the above solution for 25 minutes at -10° C.with stirring. Careful attention should be directed to the heat givenoff in the above reaction. The mixture was stirred for 20 minutes atbetween -10° to -7° C. and phosgene was removed by introducing anitrogen stream for 15 minutes at the same temperature. A solution ofdiethyl 2-hydroxyiminomalonate (3.78 g.) in benzene (20 ml.) was addedto the resultant solution containing 4-methoxybenzyl chloroformate, for10 minutes and a solution of triethylamine (5.6 ml.) in benzene (20 ml.)was added for 30 minutes at between -7° C. to -2° C. Benzene (20 ml.)was added thereto and the mixture was stirred for 30 minutes at 5° C.for 1 hour at room temperature and allowed to stand for 64 hours. Waterwas added to the reaction mixture to dissolve an insoluble material andthe organic layer was then washed with water, 3 times with a 0.5 Mcitric acid aqueous solution (20 ml.), 3 times with a 5% sodiumcarbonate aqueous solution (20 ml.) and a sodium chloride aqueoussolution, and then dried over magnesium sulfate. After drying, thesolvent was distilled off to give diethyl2-(4-methoxybenzyloxycarbonyloxyimino)malonate (5.62 g.), oil.

B. A solution of ethyl chloroformate (2.17 g.) in benzene (10 ml.) wasadded dropwise to a solution of 1-hydroxy-6-chloro-1H-benzotriazole(3.38 g.) and triethylamine (2.80 ml.) in benzene (30 ml.) underice-cooling and stirring. Benzene (30 ml.) was further added to themixture and the reaction temperature was slowly elevated to roomtemperature the mixture was allowed to stand overnight. Precipitatedcrystals were filtered off and the filtrate was concentrated. Benzenewas added to the residue and an insoluble material was filtered off. Thefiltrate was concentrated to give1-ethoxycarbonyloxy-6-chloro1H-benzotriazole (2.2 g.), crystals. Theprecipitated crystals filtered off and the insoluble material in benzenewere mixed and then washed with water, a sodium bicarbonate aqueoussolution, 1 N hydrochloric acid and water, and recrystallized frommethanol (75 ml.) to give the desired compound (3.5 g.), white needles,mp 160° to 162° C.

Analysis: C₉ H₈ N₃ O₃ Cl.: Calcd.: C, 44.73, H, 3.36, N, 17.39, Cl14.67; Found: C, 44.71, H, 3.25 N, 17.34, Cl 14.72.

C. Benzyl chloroformate (8.5 g.) was added dropwise under ice-cooling toa solution of 1-hydroxy-1H-benzotriazole (6.8 g.) and triethylamine (7.0ml.) in a mixture of benzene (100 ml.) and water (50 ml.), and themixture was stirred for 3 hours at the same temperature. The reactionmixture was filtered and the precipitated crystals were washed withwater and dried. The benzene layer was washed with water, dried andconcentrated. The residue and the crystals obtained above were mixed andrecrystallized from a mixed solvent of benzene and petroleum ether togive 1-benzyloxycarbonyloxy-1H-benzotriazole (12.1 g.), mp 130° to 131°C.

Analysis: C₁₄ H₁₁ N₃ O₃ : Calcd.: C, 62.44, H, 4.12, N, 15.61; Found: C,62.62, H, 4.16, N, 15.49.

D. A solution of benzyl chloroformate (5.1 g.) in ether (40 ml.) wasadded to a solution of 2-hydroxyimino-2-phenylacetonitrile (4.4 g.) in amixture of a 1 N potassium hydroxide aqueous solution (30 ml.) anddioxane (10 ml.) under ice-cooling. The mixture was stirred for 1 hourat the same temperature and for 4 hours at room temperature. The etherlayer was separated from the reaction mixture and the aqueous layer wasfurther extracted with ether. Both ether layers were combined, washedwith water and dried over magnesium sulfate. The solvent was distilledoff and n-hexane was added to the residue. The precipitated crystalswere collected by filtration to give2-benzyloxycarbonyloxyimino2-phenylacetonitrile (5.2 g.), mp 73° to 75°C.

Infrared Absorption Spectrum (Nujol): 1795 cm⁻¹.

E. A solution of 2,2,2-trichloroethyl chloroformate (2.2 g.) in benzene(10 ml.) was added dropwise to a solution of2-hydroxyimino-2-phenylacetonitrile (1.5 g.) and triethylamine (1.40ml.) in benzene (20 ml.) at room temperature, the mixture was stirredfor 3 hours at the same temperature. Benzene and water were added to thereaction mixture layer was washed with water and dried over magnesiumsulfate. The solvent was distilled off and the residue was crystallizedby adding a small of ether and n-hexane. The crystals were collected byfiltration and recrystallized from methanol to give2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile (2.7 g.),mp 82° to 84° C.

Infrared Absorption Spectrum (Nujol): 1800, 1790 cm⁻¹.

Analysis: C₁₁ H₇ O₃ N₂ Cl₃ : Calcd.: C, 41.08, H, 2.19, N, 8.71, Cl,33.08; Found: C, 41.29, H, 2.05, N, 8.81, Cl, 32.31.

F. The following compounds were obtained according to a method similarto those shown in Examples 3(A) to 3(E).

1. Ethyl 2-tert-butoxycarbonyloxyimininoacetoacetae, oil.

Infrared Absorption Spectrum (Film): 1780, 1730, 1690 cm⁻¹.

2. 2-tert-Butoxycarbonyloxyimino-1-phenylbutane-1,3-dione, mp 90° to103° C. (dec.).

3. 1-tert-Butoxycarbonyloxy-6-chloro-1H-benzotriazole, mp 98° to 100° C.(dec.).

4. 2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile, mp 84° to 86° C.

5. 2-(4-Methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile, mp 112°to 113° C.

6. Benzophenone O-tert-butoxycarbonyloxime, mp 131° to 133° C.

7. 2-tert-Butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile, mp 91°to 92° C.

8. 2-tert-Butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile, mp 90° to92° C.

9. 2-(1-Cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile, mp 65°to 67° C.

What we claim is: .[.1. Carbonic acid esters of the formula: carbonatoms of lower alkyl for R'₁ is 4 or 5..]. .[.2. The compounds accordingclaim 1 wherein Y' is cyano, nitro, carbamoyl, esterified carboxy, loweralkanoyl, aroyl, di-substituted carbamoyl, or aryl which may havesubstituents selected from the group consisting of lower alkoxy, nitro,cyano, and halo(lower)alkyl and Z' is aryl which may have substituentsselected from the group consisting of lower alkoxy, nitro, cyano andhalo(lower) alkyl..]. .[.3. The compounds according to claim 2, whereinR'₁ is lower alkyl which may have halogen, or ar(lower)alkyl which mayhave lower alkoxy,Y' is aryl or cyano and Z' is aryl; provided that whenR'₁ is lower alkyl Y' is cyano and Z' is aryl, the number of carbonatoms of lower alkyl for R'₁ is 4 or 5..]. .[.4. The compounds accordingto claim 3, wherein R'₁ is lower alkyl which may have halogen..].
 5. Thecompounds according to claim .[.4.]. .Iadd.30.Iaddend., wherein R'₁ islower alkyl .Iadd.having four or five carbon atoms.Iaddend..
 6. Thecompounds according to claim 5, wherein R'₁ is lower alkyl having 4 or 5carbon atoms, Y' is cyano and Z' is aryl.
 7. The compounds according toclaim 6, wherein R'₁ is tert-butyl or 1-cyclopropylethyl and Z' isphenyl; or naphthyl.
 8. The compounds according to claim 7, wherein R'₁is tert-butyl.
 9. The compound according to claim 8, wherein Z' isphenyl.
 10. The compound according to claim 8, wherein Z' is naphthyl.11. The compound according to claim 7, wherein R'₁ is 1-cyclopropylethyland Z' is phenyl.
 12. The compounds according to claim 5, wherein Y' isaryl and Z' is aryl.
 3. The compound according to claim 12, wherein R'₁is tert-butyl, Y' is phenyl and Z' is phenyl.
 14. The compoundsaccording to claim .[.4.]. .Iadd.30.Iaddend., where R'₁ is lower alkylhaving .[.halogen.]. .Iadd.at least one halogen substituent.Iaddend., Y'is cyano and Z' is aryl.
 15. The compounds according to claim 14,wherein R'₁ is ethyl having chlorine and Z' is phenyl.
 16. The compoundaccording to claim 15, wherein R'₁ is 2,2,2-trichloroethyl. .[.17. Thecompounds according to claim 3, wherein R'₁ is ar(lower)alkyl which mayhave lower alkoxy, Y' is cyano and Z' is aryl..].
 18. The compoundsaccording to claim .[.17.]. .Iadd.29.Iaddend., wherein R'₁ is benzylwhich may have methoxy .Iadd.substituents .Iaddend.and Z' is phenyl. 19.The compounds according to claim 18, wherein R'₁ is benzyl or4-methoxybenzyl.
 20. The compound according to claim 19, wherein R'₁ isbenzyl.
 21. The compound according to claim 19, wherein R'₁ ismethoxybenzyl.
 22. The compounds according to claim .[.1,.]. .Iadd.27.Iaddend.wherein R'₁ is lower alkyl, Y' is cyano and Z' is aryl havinghalogen.
 23. The compounds according to claim 22, wherein R'₁ istert-butyl and Z' is phenyl having .[.chlorine.]. .Iadd.at least onechlorine substituent.Iaddend..
 24. The compound according to claim 23,wherein Z' is 4-chlorophenyl. .Iadd.
 25. Carbonic acid esters of theformula:

    R'.sub.1 OCOOR'.sub.2

wherein R'₁ is lower alkyl which may have substituents selected from thegroup consisting of halogen, lower alkoxy and aryloxy, or ar(lower)alkyl, the aryl moiety of said ar(lower)alkyl may have substituentsselected from the group consisting of lower alkoxy, halogen, nitro andcyano, R'₂ is a group represented by the formula: ##STR7##.Iaddend.wherein Y' is selected from the group consisting of cyano, nitro,carbamoyl, lower alkanoyl, or aryl, and said aryl may have substituentsselected from the group consisting of halogen, lower alkoxy, nitro,cyano and halo (lower) alkyl, and Z' is aryl which may have substituentsselected from the group consisting of halogen, lower alkoxy, nitro,cyano and halo (lower) alkyl; provided that when R'₁ is lower alkyl, Y'is aryl or cyano, and Z' is aryl, the number of carbon atoms of loweralkyl for R'₁ is 4 or
 5. .Iadd.
 26. The compounds according to claim 25,wherein Y' is cyano, nitro, carbamoyl, lower alkanoyl, or aryl and saidaryl may have substituents selected from the group consisting of loweralkoxy, nitro, cyano, and halo (lower) alkyl and Z' is aryl which mayhave substituents selected from the group consisting of lower alkoxy,nitro, cyano and halo (lower) alkyl. .Iaddend. .Iadd.
 27. The compoundsaccording to claim 25, wherein R'₁ is lower alkyl which may have halogensubstituents, or ar(lower)alkyl, the aryl moiety of said ar(lower)alkylmay have lower alkoxy substituentsY' is cyano or aryl and Z' is arylwhich may have halogen substituents; provided that when R'₁ is loweralkyl, Y' is aryl or cyano, and Z' is aryl, the number of carbon atomsof lower alkyl for R'₁ is 4 or
 5. .Iaddend..Iadd.
 28. The compoundsaccording to claim 27, wherein Z' is aryl. .Iaddend..Iadd.
 29. Thecompounds according to claim 28, wherein R'₁ is ar(lower) alkyl, thearyl moiety of which may have lower alkoxy substituents, Y' is cyano andZ' is aryl. .Iaddend..Iadd.
 30. The compounds according to claim 28,wherein R'₁ is lower alkyl which may have one or more halogensubstituents. .Iaddend.